In 2011, bladder cancer was one of the ten most prevalent malignancies in males ranking number fourth and number eighth in terms of deaths and new cases, respectively (Siegel, Ward et al. 2011). The most common symptom of bladder cancer is hematuria, and general risk factors for the disease include smoking and carcinogen exposure (Morgan and Clark 2010). Non-muscle invasive bladder cancer (NMIBC) accounts for 80% of all the cases, and can be further classified into papillary (Ta), flat and carcinoma in situ (Tis) and subepithelial connective tissue invaded (T1) lesions. The rest of the cases present as muscle invasive bladder cancer (MIBC) (Sobin, Gospodarowicz et al. 2009, Babjuk, Oosterlinck et al. 2011). The current first line of treatment for NMIBC is transurethral resection of bladder tumor (TURBT); however, 50% of patients will recur after the TURBT procedure, with the highest rate of recurrence occurring in patients with high risk disease (Millán-Rodríguez, Chéchile-Toniolo et al. 2000, Shelley, Mason et al. 2010). As a result, TURBT patients require frequent monitoring and lifelong maintenance treatment, which makes bladder cancer one of the most costly types of cancer in terms of patient management.
The current gold standard for monitoring and treatment of bladder cancer recurrence involves the use of cystoscopy and cytology in combination with intravesical Bacile Calmette-Guerin (BCG) immunotherapy or chemotherapy (Morgan and Clark 2010, Babjuk, Oosterlinck et al. 2011). Disease surveillance is challenging because of the invasive nature of cystoscopic examination, which carries some degree of morbidity, and because of the low sensitivity displayed by urinary cytology in the detection of low-grade tumors (Lintula and Hotakainen 2010). In recent years, efforts have been devoted to find better markers of disease diagnosis and prognosis in samples collected by non-invasive methods, such as urine sediments (Sturgeon, Duffy et al. 2010). Bladder tumor cells have weaker cellular attachment than normal or benign bladder urothelium and therefore they shed more and can be collected in urine (urine sediments). However, due to their poor specificity, the markers proposed to date have not been adopted in routine clinical practice (Parker and Spiess 2011). Therefore, there is an urgent need to find reliable markers to monitor recurrence in TURBT patients, which in turn, may help facilitate and improve disease management.
More recently, it has been proposed that longitudinal collection and testing of urine sediments may help assess the prognostic, monitoring, and recurrence predictive value of markers (Hogue, Begum et al. 2006). Several studies undertook this approach by using DNA methylation analysis, microsatellite markers and a fibroblast growth factor receptor 3 (FGFR3) mutation assay (Rouprêt, Hupertan et al. 2008, Zuiverloon, van der Aa et al. 2010). Although these markers were highly sensitive, they displayed low specificity, in some cases comparable to that of cytology (Brems-Eskildsen, Zieger et al. 2010). A four DNA methylation marker panel provided better specificity; however, it also displayed a high rate of false-positive results (33%) (Zuiverloon, Beukers et al. 2012). As such, there is continued need for better, more specific and accurate testing methods for bladder cancer and bladder cancer recurrence.